Introduction. The suprachiasmatic nucleus controls the circadian rhythm of the body and disruptions of this rhythm has been linked to breast cancers. Breast cancer accounts for 25% of cancers which affect women, making it the most common malignancy in females worldwide. Based on different phenotypes, breast cancer can be divided into two main classes and four different groups. The classes and groups are divided based on the hormone status of the cancer and expression of the proto-oncogene erb-b2 receptor tyrosine kinase (ERBB2)1-2. Human mammary epithelial cells have a circadian oscillator that plays a crucial role in controlling cell cycle and cell proliferation in breast cancer. In estrogen receptor alpha positive and estrogen receptor alpha negative breast cancers the circadian rhythm of mammary epithelial cells is disrupted. Methods. Circadian locomotor output cycles kaput (CLOCK) and Brain and muscle ARNT-like 1 (BMAL1) are two main circadian proteins which form heterodimers to influence the production of Period (per), cryptochrome (cry), differentiated embryo-chondorcyte(DEC), and retinoic acid-related orphan nuclear receptor (rer-erba) proteins. Studies have shown that overexpression of Per1 is linked to DNA damage induced apoptosis and per2 reduces estrogen receptor activation having an oncostatic effect. On the other hand, other studies linked overexpression of CLOCK to increased proliferation of luminal cancer cells by estrogen- estrogen receptor alpha signaling. Results. More importantly, the CLOCK/BMAL1 heterodimer is shown to regulate cell-cycle genes through the activation of the Wee1 G2 checkpoint kinase in an oncogenic manner. Wee 1 is a kinase that helps cells transition from the G2 phase of the cell cycle to mitosis. Additionally, studies showed Cry2 roles of tumor suppression, in a Cry2 knockdown of cancer cells the result led to cell proliferation, angiogenesis and cell differentiation3-7. The link of circadian clock proteins and its influence on breast cancer tissues is clearly evident. Chronotherapy, a strategy to administer cytotoxic drugs at optimal times during the cell cycle to enhance the drugs effect is being looked into as novel way to fight cancer cells. Breast cancer growth rate has two daily peaks which correlates with the clock-controlled genes and down expression of PER1 enhances the amplitude of the daily growth peak. Conclusions. In CLOCK mutant mice and BMAL1 knockout mice the sensitivity of cyclophosphamide a chemotherapy agent was increased. Mice with with Cry knocked out showed resistance to cyclophosphamide. Using this knowledge drugs can be administered during times in the day when they are most effective2.
- Kochan D, Kovalchuk O. Circadian disruption and breast cancer: An epigenetic link. Oncotarget. 2015;6(19):866-882. doi:10.18632/oncotarget.4343.
- Li S, Ao X. The role of circadian rhythm in breast cancer. Chinese Journal of Cancer Research. 2013;25(4):442-450. doi:10.3978/j.issn.1000-9604.2013.08.19
- Reszka E, Przybek M. Circadian Genes in Breast Cancer. Advances in Clinical Chemistry. 2016;75:53-70. doi:10.1016/bs.acc.2016.03.005.
- Wang Y, Rao VK, Kok WK, et al. SUMO modification of Stra13 is required for repression of cyclin D1 expression and cellular growth arrest. PLoS One 2012;7:e43137.
- Li S, Wang M, Ao X, et al. CLOCK is a substrate of SUMO and sumoylation of CLOCK upregulates the transcriptional activity of estrogen receptor-α. Oncogene. 2012
- Gu X, Xing L, Shi G, et al. The circadian mutation PER2(S662G) is linked to cell cycle progression and tumorigenesis. Cell Death Differ 2012;19:397-405
- Xiao L, Chang AK, Zang MX, Bi H, Li S, Wang M, Xing X, Wu H. Induction of the CLOCK gene by E2-ERalpha signaling promotes the proliferation of breast cancer cells. PloS one. 2014